It is well known that the development of normal tissues and organs requires the generation of tissue-specific cells from stem cells. The maintenance of this stem cell system also requires the generation of an appropriate microenvironment. Blood vessels are the most essential structures in tissues and organs, as without blood vessel formation, almost all tissues cannot develop (there are some exceptions). In our research group, we are analyzing the molecular mechanisms by which blood vessels form in physiological and pathological conditions, including in cancers and inflammation. We are also elucidating the mechanisms that cause stem cells to associate closely with blood vessels. Ultimately, we wish to employ our results to establish strategies that will inhibit the malignant progression of various diseases. Our specific research projects are as follows:
I. Analysis of the molecular mechanism of blood vessel formation
1) Molecular analysis of sprouting angiogenesis from preexisting vessels, with a particular focus on the Tie2 receptor.
2) Identification and characterization of adult endothelial stem cells (the CD31-positive side population cells).
3) Molecular characterization of arterio-venous patterning, with a particular focus on the apelin/APJ system.
4) Development of a system that delivers drugs into blood vessels.
II. Molecular analysis of self-renewal in normal and cancer stem cells
1) Mechanism of stem cell reprogramming.
2) Analysis of cell cycle regulation in stem cells, with a special focus on Galectin-3 and the GINS complex.
3) Bioimaging of the niches that are inhabited by living cancer and normal stem cells.
4) Establishment of a strategy that can inhibit the formation of the vascular niche inhabited by cancer stem cells.
Figure 1. Vascular niche of cancer stem cells.
After treatment of a tumor with angiogenesis inhibitors, the mature blood vessels at the tumor edge persist (left panels). Cancer stem cells marked by PSF1 (a member of the GINS DNA replication factor family that is expressed by the self-renewing normal stem cell population in a variety of tissues and organ) are present and proliferate in the vascular niche represented by these mature blood vessels (right panels). Molecular analysis of vascular niche formation may be highly useful for the development of a new therapy for cancer stem cells.
Figure 2. Maturation of blood vessels at the tumor edge.
Hematopoietic stem cells (HSCs) migrate into hypoxic tissues, produce angiopoietin-1 (Ang1), and stimulate Tie2 on endothelial cells (ECs), which results in EC migration and proliferation (upper panel). Many HSCs accumulate at the edge of the tumor during the early stage of tumorigenesis and a portion of HSCs may differentiate into mural cells (MCs) and stabilize blood vessels. Ang1 from HSCs and MCs promotes the production of apelin by ECs, thereby stimulating the apelin receptor APJ on ECs. The activation of APJ induces the proliferation and assembly of ECs, resulting in blood vessel enlargement.
Figure 3. Disruption of the vascular niche in the tumor limb.
Our goal is to completely inhibit tumor growth by destroying mature blood vessels in the tumor environment. For this purpose, we need a drug delivery system that will deliver drugs that specifically block the blood vessel maturation functions of ECs in the tumor.